|Year : 2020 | Volume
| Issue : 1 | Page : 1-9
Indices of Tissue Perfusion: Triggers of Targets of Resuscitation?
Daniel De Backer1, Marie Van Hove2, Pierre Foulon3, Joe Kadou3, Gregoire Michiels3, Simone Giglioli3
1 Department of Intensive Care; Department of Emergency Medicine, CHIREC Hospitals, Université Libre De Bruxelles, Brussels, Belgium
2 Department of Emergency Medicine, CHIREC Hospitals, Université Libre De Bruxelles, Brussels, Belgium
3 Department of Intensive Care, CHIREC Hospitals, Université Libre De Bruxelles, Brussels, Belgium
|Date of Submission||21-Mar-2020|
|Date of Acceptance||20-Aug-2020|
|Date of Web Publication||31-Dec-2020|
Prof. Daniel De Backer
Department of Intensive Care, CHIREC Hospitals, Boulevard du Triomphe 201, B-1160, Brussels
Circulatory shock is characterized by a decrease in oxygen delivery to the tissues associated with impairment in oxygen metabolism and tissue hypoxia. Clinical and biological signs of impaired tissue perfusion and tissue hypoxia are used as bedside to detect circulatory failure and trigger resuscitation procedures. The most popular signs of tissue hypoperfusion include mean arterial pressure, capillary refill time and mottling score, central venous oxygen saturation (ScvO2), veno-arterial difference in PCO2 (PvaCO2), microcirculation assessment, and lactate. Both the severity and duration of the alterations in any of these variables are associated with a poor outcome so that it sounds logical to trigger therapy based on these. Using these variables as target for therapy is much more complex. Some of the limits for using some of these variables as targets include an incertitude about the target to reach (should we aim at normalizing or improving the variable, and by how much?) and the time lag between resolution of impaired tissue perfusion/hypoxia and normalization of the variable. The ideal target variable should have a well-defined end point and a rapid response time. Interestingly, hemodynamic resuscitation targeting these variables gave variable results. In this review, we will discuss the interest and limitations of the above-mentioned indices of tissue perfusion and hypoxia as trigger as well as end point of resuscitation in critically ill patients.
Keywords: Capillary refill time, central venous oxygen saturation, lactate, microcirculation, skin perfusion, veno.arterial difference in PCO2
|How to cite this article:|
De Backer D, Van Hove M, Foulon P, Kadou J, Michiels G, Giglioli S. Indices of Tissue Perfusion: Triggers of Targets of Resuscitation?. J Transl Crit Care Med 2020;2:1-9
|How to cite this URL:|
De Backer D, Van Hove M, Foulon P, Kadou J, Michiels G, Giglioli S. Indices of Tissue Perfusion: Triggers of Targets of Resuscitation?. J Transl Crit Care Med [serial online] 2020 [cited 2021 Nov 30];2:1-9. Available from: http://www.tccmjournal.com/text.asp?2020/2/1/1/305783
| Introduction|| |
Shock is characterized by an impaired perfusion to the organs, leading to an oxygen delivery (DO2) insufficient to sustain basal metabolism of the tissues., While best evaluated by the analysis of the relationship between oxygen consumption (VO2) and DO2, surrogates of tissue perfusion are often used at bedside to identify circulatory failure. When identified, hemodynamic monitoring, from noninvasive, including echocardiography, to more advanced,, is often warranted in patients with circulatory failure to measure cardiac output and its determinants, and to optimize DO2 and tissue perfusion. Perfusion indices can be used in two ways. Perfusion indices are mostly used to assess severity of the disease,,,, and thus to identify patients who may benefit from hemodynamic interventions aimed at improving tissue perfusion (Trigger). Several randomized trials have tested the value of signs to tissue perfusion for guiding resuscitation,,,, evaluating the response to therapy and sometimes indicating further interventions (target or end point of resuscitation). In this review, we will discuss to which extend clinical and biological indices of tissue perfusion can be used not only to trigger but also to guide hemodynamic resuscitation.
| Arterial Pressure|| |
Arterial pressure is a key determinant of organ perfusion. Many trials have demonstrated that the severity and duration of hypotension are associated with a poor outcome., Importantly, a shorter time is required for severe hypotension than for less severe hypotension to be associated with impaired organ function and increased risk of death. In addition, a low mean arterial pressure (MAP) and low diastolic arterial pressure (DAP) are both associated with a poor outcome so that one may question whether resuscitation should be targeted to MAP, DAP, or both? Most of the trials have investigated the impact of correcting MAP, which is considered to reflect tissue perfusion.
While nobody contests the relevance of hypotension, to which extent should it be corrected? Correction of severe hypotension is associated with improved organ perfusion, however targeting higher levels of blood pressure was not associated with improved tissue perfusion. In some selected patients without other signs of tissue hypoperfusion, not correcting mild hypotension was not associated with adverse events.
Several trials compared a low and higher targets of MAP, usually 65-70-80-85 mmHg, and none found any survival advantage for either level of blood pressure., Interestingly, in Asfar et al.'s trial targeting a higher MAP was associated with less impairment in renal function, especially in the group of previously hypertensive patients, but at the expense of a higher rate of arrhythmias and a trend to higher incidence of acute myocardial infarction. This was not confirmed in the subsequent trial by Lamontagne et al. who failed to demonstrate any difference in survival as well as in renal function or in any of the measured potential adverse outcome. Accordingly, it seems that blood pressure target should be personalized.,
Obviously, the personalization of blood pressure target should be based on other measurements than blood pressure itself. In addition, tissue perfusion may remain altered even when perfusion pressure is restored. Accordingly, other markers of tissue hypoperfusion are important to consider.
| Skin Perfusion|| |
Skin perfusion is one of the most accessible markers of tissue perfusion. It can be assessed using mottling score, capillary refill time (CRT), or evaluation of skin temperature.
The mottling score reflects local perfusion at knee level and is associated with outcome., Interestingly, even though often further impaired by vasopressors, the mottling score retains its predictive value on outcome independently of doses of vasopressor agents. While easy to perform, data using this variable as a guide to therapy remain scarce and descriptive.
The CRT is a clinical measure of tissue perfusion that rapidly respond to an intervention. A prolonged CRT is associated with a poor outcome,, even though some confounding factors may also play a role.
Even though looking simple, there are nevertheless several issues with CRT measurements. First, the interobserver variability is moderate with Kappa values around 0.40–0.56,, with limits of agreement between two observers as high as 1.9 s. Second, CRT normal values depend on age and sex., It also depends on the site where it is investigated (finger tip vs. knee or sternum) and on the duration of the pressure. Standardization of the procedure including the use of a chronometer is thus required to minimize interrater variability as it is performed in randomized trials. One may nevertheless that this may be achieved in clinical practice. Some devices are now also proposed to limit this variability, but these are not yet broadly available at bedside.
Taking into account these limitations, CRT can be used to track the evolution of patients with shock.,,, Lima et al. were the first to report that CRT rapidly respond to vasodilator agents administration. In the ANDROMEDA-SHOCK trial, CRT was assessed every 30 min for 8 h, triggering various hemodynamic interventions (fluids–vasopressors–inotropes) when abnormal. The response to the first fluid bolus in the emergency department (ED) may also help to identify septic shock patients with poor outcome, as patients failing to normalize their CRT after the first fluid bolus had a mortality of 67% for a mortality of only 9% in patients with normal or normalized CRT. These data may appear slightly caricatural, and contrast somewhat with the multicentric date of the ANDROMEDA-SHOCK trial, as 75% of these patients had an abnormal CRT (the 25th percentile was 3.0 so that 75% of the patients had an abnormal CRT at baseline) were included only after a first bolus of fluid and had a mortality of 35%.
| Skin Temperature|| |
Differences between core and toe can be used to assess peripheral tissue perfusion. Low peripheral temperature is associated with impaired outcome. This measurement is relatively complex and is markedly influenced by ambient temperature. This may perhaps explain its lack of popularity despite being around for >50 years.
| Central (ScvO2) and Mixed-Venous (SvO2) Oxygen Saturations|| |
ScvO2 and SvO2 are excellent indices of impaired cardiac output, and hence tissue perfusion. In sepsis, microcirculatory and mitochondrial alterations may comparatively increase ScvO2/SvO2, even when cardiac output is impaired, leading to a pseudo-normal ScvO2/SvO2.
Several studies have shown that a low ScvO2, which occurs in 25%–30% of patients with septic shock, is associated with a poor outcome., Time spent with a low SvO2 is also associated with a poor outcome. Even though ScvO2 is not equivalent to SvO2, it can be accepted as surrogate in the absence of pulmonary artery catheter. ScvO2 can be used to track the response to hemodynamic targeted therapies already in the ED, as soon as a central line is inserted.
Targeting SvO2 and ScvO2 has been the topic of multiple randomized trials. The first trial to be published was the a multicentric Italian trial targeting SvO2 (and also cardiac index) and demonstrating no impact of this strategy. Of note, SvO2 was normal in most patients at inclusion, probably as patients could be admitted up to 48 h after intensive care unit (ICU) admission. Timing of the intervention is likely a crucial issue. The concept of early goal directed therapy (EGDT) was then developed by Rivers et al. These authors suggested that resuscitation based on ScvO2 (target 70%) on top of usual care consisting on targets for MAP and central venous pressure and urine output) may improve outcome. In their landmark study, these authors observed a remarkable decrease in mortality rates in the intervention group. The results of this trial were unfortunately not confirmed in three large-scale randomized trials. Does this mean that this approach should be abandoned? Probably not. There were several striking differences between the positive and the negative trials. ScvO2 was low in the River's trial while it was already on target in the three negative trials so that there was limited room for improvement in the recent trials. In addition, 20% of the patients in the control group of the three negative trials were not admitted to the ICU at the end of the 6 h of EGDT; this sounds unrealistic for patients included for shock not responding to fluids and requiring vasopressors or lactate levels higher than 4 mmol/L. This suggests that less severe patients were admitted in the recent trials, even though meeting at least transiently the inclusion criteria. Hence, it is likely that the concept remains valid but that patient selection is crucial.
Another point that should not be neglected is that ScvO2 provides important information. Abnormal ScvO2, especially after institution of initial resuscitation measures, is associated with increased risk of death. This is why we should not neglect to measure ScvO2 as it helps to guide therapy, even at later stages, even if it doesn't need to be always corrected.
| Lactate|| |
Lactate is considered to reflect the onset of anaerobic metabolism. In experimental conditions, lactate increases sharply once oxygen consumption (VO2) begins to decrease in response to a decrease oxygen delivery (DO2)., Critically ill patients demonstrating VO2/DO2 dependence also present hyperlactatemia. Nevertheless, lactate can also be produced in other conditions than tissue hypoxia, especially inflammatory processes, and during beta-adrenergic stimulation, leading to an accelerated glycolysis and aerobic production of lactate.,,, Measurements of pyruvate may help to identify a hypoxic source of lactate. Rimachi et al. demonstrated in patients with cardiogenic or septic shock that hyperlactatemia is predominantly of hypoxic origin at admission and during the next few hours while at 24 h hyperlactatemia was mostly related to a decreased clearance and/or aerobic production.
Multiple studies have shown that elevated lactate levels are associated with a poor outcome, independently of its cause., Lactate is hence often used as triage in the ED. It is also used in the current definitions of septic shock.
Lactate can be used to trigger resuscitation. In particular, the Surviving Sepsis Campaign guidelines recommend the measurement of lactate at recognition of sepsis, to initiate fluid resuscitation in patients with hyperlactatemia and to reevaluate the effects of resuscitation by repeating lactate measurements. Lactate-guided resuscitation has emerged after the observation that the higher the decrease in lactate levels, the best the outcome. Targeting lactate decreases of 10%–20% every 2 h for 6–8 h have been investigated in several trials.,, In one trial, lactate-guided therapy (targeting lactate decrease by 10% every 2 h for 6 h) shown no superiority over EGDT. Another trial reported that lactate-guided therapy (targeting a 20% decrease every 2 h for 8 h) added to EGDT improved outcome compared to EGDT alone.
Hence, lactate-guided therapy is feasible and seems beneficial when added to EGDT. Lactate-guided therapy is nevertheless limited by the relatively slow decrease in lactate levels in response to therapy.
| Veno-Arterial Differences in PCO2 (PvaCO2)|| |
According to the Fick principle applied to CO2 production, VCO2 = cardiac output times veno-arterial difference in CO2 content. As CO2 content is quite difficult to measure (it can be estimated by complex formulas), most physicians use the veno-arterial difference in PCO2, or PvaCO2, even If the relationship between CO2 content and PCO2 may be influence by the Haldane effect.
In experimental conditions, PvaCO2 rises sharply when VO2 becomes dependent on DO2, close to the point at which lactate rises. In critically ill patients, PvaCO2 has been found to be associated with indices of tissue hypoperfusion and seems particularly attractive when ScvO2 is close to target. In addition, the presence of an increased PvaCO2 may reflect microcirculatory alterations when ScvO2 is normalized. Algorithms have been proposed to interpret increased PvaCO2 gradients together with ScvO2, separating the systemic and microcirculatory flow components.
Multiple studies have reported the prognostic value of PvaCO2, and persistent increases in PvaCO2 is associated with poor outcome.,,
Interestingly, PvaCO2 provides additional information to lactate and may be useful to interpret hyperlactatemia [Figure 1]. As PvaCO2 improves more rapidly than lactate, normal PvaCO2/high lactate represents a state in which tissue perfusion is adequate and lactate elevated either as a consequence of a resolved hypoxic event (lactate clearance is slow) or due to nonanaerobic production (adrenergic stimulation or inflammatory processes). On the other hand, an elevated PvaCO2 with normal lactate suggest an impaired tissue perfusion non yet leading to tissue hypoxia. Finally, dividing PvaCO2 by arterio-venous difference in O2 (AVDO2) reflects respiratory quotient, and an elevated respiratory quotient is present in tissue hypoxia. In patients with septic shock receiving fluid administration, an increased PvaCO2/AVDO2 was associated with an increase in VO2 so that it can be used to detect tissue hypoxia and VO2/DO2 dependency. In septic shock patients, elevated PvaCO2/AVDO2 was associated with a poor outcome and provided additional information compared to lactate.
To which extent PvaCO2 can be used as a target of resuscitation? PvaCO2 is a dynamic measurement, rapidly responding to therapeutic interventions. PvaCO2 usually decreases in response to dobutamine administration, up to a point where VO2 increases due to excessive metabolic effects of the beta-adrenergic agent., PvaCO2 as well as CRT normalizes before normalization of lactate in adequately resuscitated patients with septic shock. A randomized trial found no benefit of a PvaCO2-targeted therapy compared to EGDT in sepsis. However, the interest of PvaCO2 becomes more obvious when combining these measurements with ScvO2 rather than instead of ScvO2. At this stage, no large-scale randomized trial has tested the impact of a PvaCO2-targeted resuscitation on the top of EGDT on outcome.
| Microcirculation|| |
The microcirculation is the key determinant of tissue perfusion. De Backer et al. first demonstrated in 2002 that the microcirculation is altered in patients with septic shock. These alterations were characterized by a decrease in capillary perfusion, with huge heterogeneity within the sampled area (stopped flow capillaries are present in close vicinity of adequately perfused vessels). These results have now been replicated in more than thirty studies by various teams throughout the world. Importantly, microvascular alterations are associated with poor outcome.,,,
Importantly, these alterations were dissociated from central hemodynamics and could thus not be predicted from classical hemodynamic tools. Nevertheless, there was a good relationship between PvaCO2 and microvascular perfusion so that PvaCO2 can be used to detect microvascular alterations.
While there is no doubt that microcirculatory alterations are contributing to impaired outcome and that microvascular perfusion improves in patients with favorable outcome, microcirculatory targeted resuscitation is not yet feasible. We need first to and to better report which drugs should be used to improve the microvascular perfusion. Fluids, dobutamine, and vasoactive agents have variable effects with beneficial effects in some but not all patients.,,,, Some agents modulating endothelial function demonstrated interesting results in experimental models, but these need to be replicated in critically ill patients. We need also to define what would be the microcirculatory target value (normalization vs. improvement by xx%?).
| Lactate Versus Capillary Refill Time Versus ScvO2 Versus an Integrative Approach? Lessons from the ANDROMEDA-SHOCK Trial|| |
In a multicentric randomized trial including 424 patients with septic shock, CRT-guided therapy was compared to lactate-guided therapy. The goals were to normalize CRT (<3 s) in the CRT group and to normalize or to decrease lactate levels by 20% every 2 h in the lactate group. Mortality by day 28 was 34.9% in the CRT group and 43.4% in the lactate group, but this difference failed to reach statistical significance (P = 0.06). In a Bayesian analysis, the mortality difference was found to be significant.
What may explain the differences between lactate-guided and CRT-guided therapy? As CRT and lactate were used to guide therapy, differences in therapy likely explain the differences in outcome. As in the CRT group lactate decreased more rapidly than in the lactate-guided group, this suggest that the interventions were implemented more efficiently when triggered by CRT compared with lactate. Differences in the amount of fluid administered are unlikely to explain differences in outcome even though significant (around 400 mL lower in CRT than in lactate group). On the other hand, vasopressors tests were more frequently performed in the lactate group than in the CRT group (used in 40% of the patients in lactate group and in 29% in CRT group). If anything, this would suggest that CRT assessment prevented the implementation rather than triggering additional interventions. The alternative explanation is that the interventions may have been implemented in a more timely fashion in the CRT group. Indeed, CRT was assessed every 30 min while lactate was assessed every 2 h so that there was a possibility to implement or to stop therapies more frequently.
This study should not be misinterpreted. It does not mean that lactate should not be measured anymore and that resuscitation should be guided on CRT only. In a recent observational study, CRT and clinical sings predicted very poorly the occurrence of acute kidney injury, but the addition of lactate in the model allowed to reach satisfactory predictive value. In the ANDROMEDA-SHOCK trial, patients were included as they presented with hyperlactatemia (≥2.0 mmol/L was mandated as an inclusion criteria), so the study does not evaluate whether CRT-guided therapy is safe in patients without hyperlactatemia. In patients with normal lactate levels and impaired CRT, there is a risk of overtreating patients in whom the impaired tissue perfusion has no major consequences on metabolism. Lactate also decreased more rapidly in the CRT than lactate group, confirming the intrinsic value of this measurement in reflecting the adequacy of the resuscitation in the CRT.
Accordingly, it sounds wise to integrate several variables such as CRT, lactate, but also ScvO2 and PvaCO2 and not to rely only on one marker, taking into account the limitations of each marker [Table 1]. The different time course of these variables should be taken into account, as these demonstrate different normalization rates in septic shock survivors, with usually an initial rapid improvement, followed by a much slower trend thereafter. One should continue to try to improve tissue perfusion when several of these variables remain altered but should refrain to intervene when most variables are normalized.
|Table 1: Advantage and limits of the various indices of tissue perfusion|
Click here to view
| Conclusions|| |
Multiple indices can be used to detect impaired tissue perfusion and most are associated with outcome. While these indices can be used to detect which patients may potentially benefit from additional interventions, the lack of clear definition of what is the best value to trigger for some markers and the reaction time of others make some indices less suitable for being used as targets. Nevertheless, given the additive information of the various indices, it is advisable to use several markers in combination than using one in isolation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Vincent JL, De Backer D. Circulatory shock. N Engl J Med 2013;369:1726-34.
Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, et al
. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 2014;40:1795-815.
Vincent JL, De Backer D. My paper 20 years later: Effects of dobutamine on the VO(2)/DO(2) relationship. Intensive Care Med 2014;40:1643-8.
De Backer D. Detailing the cardiovascular profile in shock patients. Crit Care 2017;21:311.
Teboul JL, Saugel B, Cecconi M, De Backer D, Hofer CK, Monnet X, et al
. Less invasive hemodynamic monitoring in critically ill patients. Intensive Care Med 2016;42:1350-9.
De Backer D, Fagnoul D, Herpain A. The role of invasive techniques in cardiopulmonary evaluation. Curr Opin Crit Care 2013;19:228-33.
De Backer D, Hajjar LA, Pinsky MR. Is there still a place for the SwanGanz catheter? We are not sure. Intensive Care Med 2018;44:960-2.
Ait-Oufella H, Joffre J, Boelle PY, Galbois A, Bourcier S, Baudel JL, et al
. Knee area tissue oxygen saturation is predictive of 14-day mortality in septic shock. Intensive Care Med 2012;38:976-83.
Ait-Oufella H, Lemoinne S, Boelle PY, Galbois A, Baudel JL, Lemant J, et al
. Mottling score predicts survival in septic shock. Intensive Care Med 2011;37:801-7.
Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, et al
. Lactate measurements in sepsis-induced tissue hypoperfusion: Results from the Surviving Sepsis Campaign database. Crit Care Med 2015;43:567-73.
Vincent JL, Nielsen ND, Shapiro NI, Gerbasi ME, Grossman A, Doroff R, et al
. Mean arterial pressure and mortality in patients with distributive shock: A retrospective analysis of the MIMIC-III database. Ann Intensive Care 2018;8:107.
Hernández G, Cavalcanti AB, Ospina-Tascón G, Zampieri FG, Dubin A, Hurtado FJ, et al
. Early goal-directed therapy using a physiological holistic view: The ANDROMEDA-SHOCK-a randomized controlled trial. Ann Intensive Care 2018;8:52.
Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, et al
. Early lactate-guided therapy in intensive care unit patients: A multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010;182:752-61.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al
. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, et al
. A systematic review and meta-analysis of early goal-directed therapy for septic shock: The ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 2015;41:1549-60.
Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettilä V. Hemodynamic variables related to outcome in septic shock. Intensive Care Med 2005;31:1066-71.
Benchekroune S, Karpati PC, Berton C, Nathan C, Mateo J, Chaara M, et al
. Diastolic arterial blood pressure: A reliable early predictor of survival in human septic shock. J Trauma 2008;64:1188-95.
Albanèse J, Leone M, Garnier F, Bourgoin A, Antonini F, Martin C. Renal effects of norepinephrine in septic and nonseptic patients. Chest 2004;126:534-9.
Bourgoin A, Leone M, Delmas A, Garnier F, Albanèse J, Martin C. Increasing mean arterial pressure in patients with septic shock: Effects on oxygen variables and renal function. Crit Care Med 2005;33:780-6.
Lavillegrand JR, Dumas G, Bigé N, Zafimahazo D, Guidet B, Maury E, et al
. Should we treat mild hypotension in septic patients in the absence of peripheral tissue hypoperfusion? Intensive Care Med 2018;44:1593-4.
Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, et al
. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014;370:1583-93.
Lamontagne F, Richards-Belle A, Thomas K, Harrison DA, Sadique MZ, Grieve RD, et al
. Effect of reduced exposure to vasopressors on 90-day mortality in older critically Ill patients with vasodilatory hypotension: A randomized clinical trial. JAMA JAMA 2020;323:938-49.
De Backer D, Cecconi M, Lipman J, Machado F, Myatra SN, Ostermann M, et al
. Challenges in the management of septic shock: A narrative review. Intensive Care Med 2019;45:420-33.
De Backer D, Foulon P. Minimizing catecholamines and optimizing perfusion. Crit Care 2019;23:149.
Ait-Oufella H, Bakker J. Understanding clinical signs of poor tissue perfusion during septic shock. Intensive Care Med 2016;42:2070-2.
Ait-Oufella H, Bourcier S, Alves M, Galbois A, Baudel JL, Margetis D, et al
. Alteration of skin perfusion in mottling area during septic shock. Ann Intensive Care 2013;3:31.
Jouffroy R, Saade A, Tourtier JP, Gueye P, Bloch-Laine E, Ecollan P, et al
. Skin mottling score and capillary refill time to assess mortality of septic shock since pre-hospital setting. Am J Emerg Med 2019;37:664-71.
Dumas G, Lavillegrand JR, Joffre J, Bigé N, de-Moura EB, Baudel JL, et al
. Mottling score is a strong predictor of 14-day mortality in septic patients whatever vasopressor doses and other tissue perfusion parameters. Crit Care 2019;23:211.
Lima A, van Genderen ME, van Bommel J, Klijn E, Jansem T, Bakker J. Nitroglycerin reverts clinical manifestations of poor peripheral perfusion in patients with circulatory shock. Crit Care 2014;18:R126.
Ait-Oufella H, Bige N, Boelle PY, Pichereau C, Alves M, Bertinchamp R, et al
. Capillary refill time exploration during septic shock. Intensive Care Med 2014;40:958-64.
Oskay A, Eray O, Dinç SE, Aydın AG, Eken C. Prognosis of critically ill patients in the ED and value of perfusion index measurement: A cross-sectional study. Am J Emerg Med 2015;33:1042-4.
Alsma J, van Saase JL, Nanayakkara PW, Schouten WE, Baten A, Bauer MP, et al
. The power of flash mob research: Conducting a nationwide observational clinical study on capillary refill time in a single day. Chest 2017;151:1106-13.
Brabrand M, Hosbond S, Folkestad L. Capillary refill time: A study of interobserver reliability among nurses and nurse assistants. Eur J Emerg Med 2011;18:46-9.
Espinoza ED, Welsh S, Dubin A. Lack of agreement between different observers and methods in the measurement of capillary refill time in healthy volunteers: An observational study. Rev Bras Ter Intensiva 2014;26:269-76.
Schriger DL, Baraff L. Defining normal capillary refill: Variation with age, sex, and temperature. Ann Emerg Med 1988;17:932-5.
Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, et al
. Effect of a resuscitation strategy targeting peripheral perfusion status vs. Serum lactate levels on 28-day mortality among patients with septic shock: The ANDROMEDA-SHOCK randomized clinical trial. JAMA 2019;321:654-64.
Shinozaki K, Jacobson LS, Saeki K, Hirahara H, Kobayashi N, Weisner S, et al
. Comparison of point-of-care peripheral perfusion assessment using pulse oximetry sensor with manual capillary refill time: Clinical pilot study in the emergency department. J Intensive Care 2019;7:52.
Hernandez G, Luengo C, Bruhn A, Kattan E, Friedman G, Ospina-Tascon GA, et al
. When to stop septic shock resuscitation: Clues from a dynamic perfusion monitoring. Ann Intensive Care 2014;4:30.
Lara B, Enberg L, Ortega M, Leon P, Kripper C, Aguilera P, et al
. Capillary refill time during fluid resuscitation in patients with sepsis-related hyperlactatemia at the emergency department is related to mortality. PLoS One 2017;12:e0188548.
Bourcier S, Pichereau C, Boelle PY, Nemlaghi S, Dubée V, Lejour G, et al
. Toe-to-room temperature gradient correlates with tissue perfusion and predicts outcome in selected critically ill patients with severe infections. Ann Intensive Care 2016;6:63.
Joly HR, Weil MH. Temperature of the great toe as an indication of the severity of shock. Circulation 1969;39:131-8.
Boulain T, Garot D, Vignon P, Lascarrou JB, Desachy A, Botoc V, et al
. Prevalence of low central venous oxygen saturation in the first hours of intensive care unit admission and associated mortality in septic shock patients: A prospective multicentre study. Crit Care 2014;18:609.
Rady MY, Rivers EP, Martin GB, Smithline H, Appelton T, Nowak RM. Continuous central venous oximetry and shock index in the emergency department: Use in the evaluation of clinical shock. Am J Emerg Med 1992;10:538-41.
Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, et al
. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2
Collaborative Group. N Engl J Med 1995;333:1025-32.
De Backer D, Vincent JL. Early goal-directed therapy: Do we have a definitive answer? Intensive Care Med 2016;42:1048-50.
Protti A, Masson S, Latini R, Fumagalli R, Romero M, Pessina C, et al
. Persistence of central venous oxygen desaturation during early sepsis is associated with higher mortality: A retrospective analysis of the ALBIOS trial. Chest 2018;154:1291-300.
Vincent JL, De Backer D. From Early Goal-Directed Therapy to Late® 2checks. Chest 2018;154:1267-9.
De Backer D, Roman A, Van der Linden P, Armistead C, Schiltz G, Vincent JL. The effects of ballon filling into the inferior vena cava on the VO2
relationship. J Crit Care 1992;7:167-73.
Zhang H, Rogiers P, De Backer D, Spapen H, Manikis P, Schmartz D, et al
. Regional arteriovenous differences in PCO2
and pH can reflect critical organ oxygen delivery during endotoxemia. Shock 1996;5:349-56.
Vincent JL, Roman A, De Backer D, Kahn RJ. Oxygen uptake/supply dependency. Effects of short-term dobutamine infusion. Am Rev Respir Dis 1990;142:2-7.
De Backer D. Lactic acidosis. Intensive Care Med. 2003;29:699-702.
Levy B, Desebbe O, Montemont C, Gibot S. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock 2008;30:417-21.
Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE. Relation between muscle Na+K+ATPase activity and raised lactate concentrations in septic shock: A prospective study. Lancet 2005;365:871-5.
Gore DC, Jahoor F, Hibbert JM, DeMaria EJ. Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability. Ann Surg 1996;224:97-102.
Rimachi R, Bruzzi de Carvahlo F, Orellano-Jimenez C, Cotton F, Vincent JL, De Backer D. Lactate/pyruvate ratio as a marker of tissue hypoxia in circulatory and septic shock. Anaesth Intensive Care 2012;40:427-32.
Weil MH, Afifi AA. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation 1970;41:989-1001.
Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al
. Developing a new definition and assessing new clinical criteria for septic shock: For the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:775-87.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al
. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-77.
Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA, et al
. Lactate clearance vs. central venous oxygen saturation as goals of early sepsis therapy: A randomized clinical trial. JAMA 2010;303:739-46.
Bakker J, De Backer D, Hernandez G. Lactate-guided resuscitation saves lives: We are not sure. Intensive Care Med 2016;42:472-4.
Vallée F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, et al
. Central venous-to-arterial carbon dioxide difference: An additional target for goal-directed therapy in septic shock? Intensive Care Med 2008;34:2218-25.
Ospina-Tascón GA, Umaña M, Bermúdez WF, Bautista-Rincón DF, Valencia JD, Madriñán HJ, et al
. Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Med 2016;42:211-21.
Perner A, Gordon AC, De Backer D, Dimopoulos G, Russell JA, Lipman J, et al
. Sepsis: Frontiers in diagnosis, resuscitation and antibiotic therapy. Intensive Care Med 2016;42:1958-69.
Ospina-Tascón GA, Bautista-Rincón DF, Umaña M, Tafur JD, Gutiérrez A, García AF, et al
. Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock. Crit Care 2013;17:R294.
Du W, Liu DW, Wang XT, Long Y, Chai WZ, Zhou X, et al
. Combining central venous-to-arterial partial pressure of carbon dioxide difference and central venous oxygen saturation to guide resuscitation in septic shock. J Crit Care 2013;28:1110.e1-5.
Mallat J, Pepy F, Lemyze M, Gasan G, Vangrunderbeeck N, Tronchon L, et al
. Central venous-to-arterial carbon dioxide partial pressure difference in early resuscitation from septic shock: A prospective observational study. Eur J Anaesthesiol 2014;31:371-80.
Monnet X, Julien F, Ait-Hamou N, Lequoy M, Gosset C, Jozwiak M, et al
. Lactate and venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio, but not central venous oxygen saturation, predict increase in oxygen consumption in fluid responders. Crit Care Med 2013;41:1412-20.
Ospina-Tascon GA, Umana M, Bermudez W, Bautista-Rincon DF, Hernandez G, Bruhn A, et al
. Combination of arterial lactate levels and venous-arterial CO to arterial-venous O content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med 2015;41:796-805.
Teboul JL, Mercat A, Lenique F, Berton C, Richard C. Value of the venous-arterial PCO2
gradient to reflect the oxygen supply to demand in humans: Effects of dobutamine. Crit Care Med 1998;26:1007-10.
Mallat J, Benzidi Y, Salleron J, Lemyze M, Gasan G, Vangrunderbeeck N, et al
. Time course of central venous-to-arterial carbon dioxide tension difference in septic shock patients receiving incremental doses of dobutamine. Intensive Care Med 2014;40:404-11.
Su L, Tang B, Liu Y, Zhou G, Guo Q, He W, et al
-directed resuscitation does not improve prognosis compared with SvO2
in severe sepsis and septic shock: A prospective multicenter randomized controlled clinical study. J Crit Care. 2018;48:314-20.
De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002;166:98-104.
Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL. Persistant microvasculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004;32:1825-31.
De Backer D, Donadello K, Sakr Y, Ospina-Tascon G, Salgado D, Scolletta S, et al
. Microcirculatory alterations in patients with severe sepsis: Impact of time of assessment and relationship with outcome. Crit Care Med 2013;41:791-9.
Trzeciak S, McCoy JV, Phillip Dellinger R, Arnold RC, Rizzuto M, Abate NL, et al
. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 2008;34:2210-7.
De Backer D, Creteur J, Dubois MJ, Sakr Y, Koch M, Verdant C, et al
. The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 2006;34:403-8.
Ospina-Tascon G, Occhipinti G, Oliveira Silva T, Buchele G, Vincent JL, De Backer D. Effects of fluid challenge on microcirculatory alterations in early severe sepsis and septic shock. Intensive Care Med 2007;33:S125.
Sakr Y, Chierego M, Piagnerelli M, Verdant C, Dubois MJ, Koch M, et al
. Microvascular response to red blood cell transfusion in patients with severe sepsis. Crit Care Med 2007;35:1639-44.
Donati A, Damiani E, Luchetti M, Domizi R, Scorcella C, Carsetti A, et al
. Microcirculatory effects of the transfusion of leukodepleted or non-leukodepleted red blood cells in patients with sepsis: A pilot study. Crit Care 2014;18:R33.
Boerma EC, Koopmans M, Konijn A, Kaiferova K, Bakker AJ, van Roon EN, et al
. Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: A double-blind randomized placebo controlled trial. Crit Care Med 2010;38:93-100.
He X, Su F, Velissaris D, Salgado DR, de Souza Barros D, Lorent S, et al
. Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock. Crit Care Med 2012;40:2833-40.
Tyml K, Li F, Wilson JX. Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med 2005;33:1823-8.
Zampieri FG, Damiani LP, Bakker J, Ospina-Tascon GA, Castro R, Cavalcanti AB, et al
. Effect of a resuscitation strategy targeting peripheral perfusion status vs. serum lactate levels on 28-day mortality among patients with septic shock: A bayesian reanalysis of the ANDROMEDA-SHOCK trial. Am J Respir Crit Care Med 2020;201:423-9.
Wiersema R, Koeze J, Eck RJ, Kaufmann T, Hiemstra B, Koster G, et al
. Clinical examination findings as predictors of acute kidney injury in critically ill patients. Acta Anaesthesiol Scand 2020;64:69-74.